ABSTRACT: This application is a Phase I/Phase II Fast-Track SBIR application. Osteoarthritis (OA), the clinical syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joint disease. There are no consistently effective methods for preventing OA or slowing its progression, and so symptomatic treatments represent the standard of care, the foundation of which are the non-steroidal anti-inflammatory drugs (NSAIDs). Such treatments for OA require consideration of not only gastrointestinal (GI) risk, but also cardiovascular (CV) risk; non-selective NSAIDs acting on both cyclooxygenase-1 (COX-1) and COX-2 universally increase the risk of GI injury, whereas nearly all NSAIDs, especially the selective COX-2 inhibitors, have been shown to increase the risk of serious CV events. The withdrawal of rofecoxib and valdecoxib from the market amplify the continuing need for an NSAID with minimal CV and GI risks. Naproxen has become the NSAID of choice for most mild/moderate chronic inflammatory indications, including OA, as it appears to have little or no increased risk of cardiovascular adverse events. However, in spite of its favorable CV safety profile, naproxen is well known to induce GI toxicity that is sometimes life-threatening. The activities proposed in this grant application are intended to advance a new naproxen formulation (Naproxen-PC) that not only improves the GI safety of naproxen using a non-COX mechanism, but also may enhance anti-inflammatory activity compared with naproxen. Naproxen-PC improves GI safety by increasing the lipophilicity of the NSAID via non- covalent pre-association with a surface-active phospholipid, namely phosphatidylcholine (PC). This oil-based formulation of PC-associated naproxen (Naproxen-PC) has been shown in rodent models to have remarkably lower (~85%) GI toxicity, while retaining the efficacy and general safety profile of unmodified naproxen. Recently, novel methods have been developed to profile bioactive lipids in a model of joint inflammation, including products of both cyclooxygenase (COX) and lipoxygenase (LOX). Preliminary data assaying a range of bioactive lipids suggests that Naproxen-PC may have enhanced anti-inflammatory efficacy, as reflected in the attenuation of pro-inflammatory eicosanoids (including prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 12- hydroxyeicosatetraenoic acid (12-HETE), and 5-HETE), while sparing anti-inflammatory eicosanoids (13- hydroxyoctadecadienoic acid (13-HODE)), compared with unmodified naproxen, in a rodent model of joint inflammation. The major objective of this Fast-Track SBIR application is to confirm the preliminary data described above and continue and expand the development of Naproxen-PC and initiate clinical studies. In Phase I, initial activities will focus on expanding and confirming the enhanced anti-inflammatory activity of Naproxen-PC seen in animal models. Also, in partnership with a commercial manufacturer, we propose to optimize the laboratory formulation of Naproxen-PC so that it may be softgel encapsulated and manufactured for clinical trials. Several lead prototypes resulting from this optimization will be identified that appear commercially viable, which will be tested in established animal models with both GI safety and analgesic and anti-inflammatory efficacy endpoints. The results of these experiments will allow selection of a single, validated lead Naproxen-PC formulation. In Phase II, the lead formulation will be manufactured as 250 mg Naproxen-PC gelcaps according to regulatory standards, further tested for stability, then advanced into clinical trials. Initially, a single-dose bioequivalence (BE) study, comparing Naproxen-PC with unmodified naproxen, will be completed in healthy volunteers; this pharmacokinetics study will provide BE data for Naproxen-PC FDA approval via the accelerated 505(b)(2) regulatory route, and provide data on the systemic safety of Naproxen- PC. Then, a comparative proof-of-concept clinical trial will be conducted examining analgesic efficacy, general safety and the incidence of gastrointestinal ulcers, assessed endoscopically, in patients with osteoarthritis aged 55 years or older, following administration of 500 mg Naproxen-PC or naproxen BID for 12 weeks. The development activities encompassed in this grant proposal will significantly advance the Naproxen-PC development toward commercialization. If the Naproxen-PC formulation is shown in subsequent confirmatory clinical trials to possess an improved GI safety profile, together with equivalent analgesic and perhaps superior anti-inflammatory efficacy compared with naproxen, it will represent an important new treatment for patients with osteoarthritis and related chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE Nearly all currently available non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, ibuprofen, and aspirin, cause significant GI damage, which results in a large number of hospitalizations and deaths annually. At the same time, many millions of Americans need daily treatment for arthritis and related conditions. This grant request is to allow the continued development of Naproxen-PC, a new formulation of naproxen that significantly reduces GI injury, even when taken repeatedly. Naproxen has become the NSAID of choice for repeated administration, including in the treatment of osteoarthritis, because unlike almost all other NSAIDs, it doesn't increase the possibility of heart attack, stroke, or other cardiovascular events. [unreadable] [unreadable] [unreadable]